The city's Office of Emergency Management says it is responding to reports of an explosion at John F. Kennedy High School in the Marble Hill section of Manhattan.
OEM says the school is located at 99 Terrace View Avenue.
Con Edison said they are still investigating whether the explosion was gas-related, but that gas was turned off as a precaution.
Officials say they believe the explosion originated in a science lab.
According to OEM, three classrooms on the fourth, fifth and sixth floors were damaged.
Fire officials say three people were transported to Jacobi Hospital with burns. Officials say one of the workers is more seriously injured than the others but the injuries are not considered life-threatening.
Witnesses said they first thought there had been an earthquake.
"It felt like a giant truck ran into my house. And I ran outside and all my neighbors ran outside and we thought it was an earthquake at first. And then we started hearing all the fire trucks and the sirens and my neighbors, we went and discovered that there was an explosion at JFK High School," one witness said.
"Very serious burns for those workers. Our hearts go out to them and their families. This school obviously has sustained some very, very serious damage. This was part of a project being run by the school construction authority through a private contractor," de Blasio said.
"We have people from Department of Buildings, engineers making a further evaluation, our fire marshals and their counterparts in NYPD are doing an investigation as we speak behind us. And our thoughts and prayers are with the three injured contractors," said Fire Commissioner Daniel Nigro.
Still no word on whether the explosion will affect the start of the school year.